February 11, 2010

Many of you have been sold a bill of goods about how you "caused your diabetes" with unhealthy lifestyle choices. The media are full of articles telling us that diabetes is caused by obesity and failure to exercise which cause insulin resistance. You might have been told that while people with Type 1 Diabetes don't secrete insulin, people with Type 2 Diabetes secrete too much insulin. Though doctors repeat this misinformation, it turns out not to be true.

High quality research suggests very strongly that most Type 2 Diabetes results from genetic damage. This damage may be inherited or it may be caused by environmental pollutants like arsenic, PCBs, pesticides and popular prescription drugs. The environment of the womb can also permanently alter the expression of certain genes in ways that promote the development of Type 2 Diabetes.

Since the research has made it clear that most Type 2 is inherited, scientists have been using the new, cheap tools for studying the genome, to search for the gene variants that are common among people with Type 2 diabetes and absent in the rest of the population.

The single most common Type 2 Diabetes gene they've found in populations of people with Western European heritages is a variant of TCF7L2. A study published in this month's edition of the journal Diabetes sheds much light on why this gene is so closely associated with (i.e. causes) Type 2 Diabetes. You can find the study here:

First off, ignore the article's title. As is becoming more and more common, the titles of research studies are being slanted to appeal to whatever the fashionable belief of the year might be in diabetes research. And as is also common, that fashionable belief is heavily influenced by the mechanisms used by whatever new drugs are being peddled by Big Pharma. Since right now incretin drugs are the hottest (i.e. most expensive) new drugs, the researchers pitched this article as if it was a study documenting the effect of the defective TCF7L2 gene on incretin hormones. In fact, its results show something else entirely.

What the researchers did here was take eight subjects with the specific variant of the TCF7L2 gene that has been linked to Type 2 diabetes and compare them to a group of 10 controls lacking this gene variant. The tool used was a fancy 5 hour glucose tolerance test. (Yes, I know this is a pitifully small sample which makes its result suspect, and thanks for noticing.)

The isoglycemic infusion is one where glucose levels are maintained at a constant level. In the graded glucose infusion the glucose amount is raised in steps in amounts that are usually calculated as a function of the subject's body weight. This is because glucose raises blood sugar in inverse proportion to the subject's body weight: the more a person weighs, the less rise there is with each additional gram of glucose.

Note that the researchers made no direct measurement of the incretin hormones, GLP-1 and GIP in the course of the study. They drew their conclusions about incretin hormones after applying a mathematical model to the glucose tolerance test results.

As stated in the study:

The incretin effect was assessed from ratios of the insulin secretory rates (ISR) during oral and isoglycemic glucose infusions.

This strikes me as an odd way to determine the effect of incretin hormones. I'm sure the model was based on the findings of some other study, but without direct measurement of the incretin hormones the conclusion has to be labeled, at best, "speculative".

So let's ignore that for now, and see what we can safely conclude from this fancy glucose tolerance test. And it turns out that it is something worth noting. The study found that

This means the TCF7L2 gene carried by so many people with Type 2 diabetes damages the ability of the beta cell to secrete insulin in response to rising blood sugars.

If so, we can define TCF7L2-related Type 2 Diabetes as a disease of insulin insufficiency, NOT, as we are usually told, a disease caused by insulin resistance.

The headlined conclusion of this study, based on the estimates of "incretin effect" derived from the mathematical model is that:

The TCF7L2 variant rs7903146 appears to affect risk of type 2 diabetes, at least in part, by modifying the effect of incretins on insulin secretion. This is not due to reduced secretion of GLP-1 and GIP but rather due to the effect of TCF7L2 on the sensitivity of the β-cell to incretins.

This translates into saying that normal amounts of incretin hormones are being made, but the beta cell isn't responding to them. Given that this conclusion is drawn without any measuring of incretin hormone levels, the only part of this statement that is reliable is the "at least in part" which translates into, "Perhaps, maybe."

In any case, this is not the first study to find that the common genes associated with Type 2 Diabetes cause failure to secrete insulin, NOT insulin resistance. The more research done into these genes, the more the balance is shifting to finding that Type 2 Diabetes is often an insulin deficiency disease.

You can read about the research that had identified the common Type 2 Diabetes genes in this excellent summary:

Note this extremely interesting statement from the lead researcher in this large scale effort to find Type 2 Diabetes genes:

"The hallmarks of type 2 diabetes are insulin resistance and impaired beta cell function. We were intrigued to find that most of the newly found variants influence insulin secretion rather than insulin resistance. Only one variant, near IGF1, is associated with insulin resistance," said lead author Inês Barroso, Ph.D., of the Wellcome Trust Sanger Institute, Cambridge, England.

You can read about much more research that links Type 2 Diabetes to genetic flaws both inherited and caused by environmental pollutants on the web page,

8
comments:

Maybe. On the one hand, I've known many T2's on insulin. Almost all are overweight (or gained weight after starting insulin), and BG in better control, but not tight.

On the other hand, I've had my insulin measured. There's too much floating about, not doing what it is supposed to do. My brain can't wrap itself around the assertion that I should add more to the mix. Interesting studies, though. I'll read them again.

How would this relate to weight gain and IR. The mystery deepens. A U of WA researcher a few years ago mentioned after a study that they knew diabetes was poorly understood, but that after the study they understood it less. (mangled quote, I may try to find the original)

When blood sugar stays over 180 mg/dl for long periods of time, we develop "secondary IR" in response to the high blood sugar and this can promote weight gain even in people who are otherwise not IR.

Insulin also turns out to regulate the way the hypothalamus regulates energy burning, and of course, many people with Type 2 have bad thyroids which cause weight gain independent of diet.

Weight regulation is extremely complex--much more complex than any of the books on the topic would suggest. I put some time into studying the research and concluded that there was no way I could write anything on the subject that would do anything but depress the reader.

What I have been seeing from the technical media is an indication that there are multiple causes of what we call "Type 2 Diabetes". I believe we may be talking about three or more separate and distinct conditions that are all called "Type 2 Diabetes". One is a more severe variety of Impaired Glucose Tolerance (IGT) -- which is what this particular test seemed to measure. David Edelman wrote last year about a type of insulin-resistance-related diabetes brought about by a genetic switch that caused improperly-folded insulin. Then there is the "Type 2" that is moderated by lipokines which interrupt the leptin/ghrelin/insulin metabolism. (Whether the growth of adipose tissue is "our own fault" or not is another issue; a recent press release suggests that T2s have a damaged gene that impairs our ability to resist impulses and self-gratification... need to look up the original on that one!)

That not all T2 patients at the same stage of development respond to the same classes of oral antidiabetic should be considered empirical evidence towards the development of a "multiple types of T2" hypothesis.

You are citing poor sources for causes of diabetes. The idea that "there is the "Type 2" that is moderated by lipokines which interrupt the leptin/ghrelin/insulin metabolism" is not well documented for people, just for rodents which have a very different lipid metabolism than people.

The cause you mentioned David Edelman commenting about is obscure and not found in 99% of people with Type 2.

Unfortunately, there is a lot of speculation about the causes of diabete in the health media which are 99% derived from rodent studies where people draw sweeping conclusions based more on their religious belief that people with diabetes are lazy gluttons than on the science.

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I was diagnosed with diabetes in 1998. Since then I've kept my A1cs in the 5.0-6.0% range using the techniques you'll find explained at The main Blood Sugar 101 Web Site, where you'll also find extensive discussion of the peer-reviewed research that backs up the statements you read here.

I've also published two books on related subjects, Blood Sugar 101: What They Don't Tell You About Diabetes, which was an Amazon Diabetes bestseller for 3 years and Diet 101: The Truth About Low Carb Diets.